ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.665C>G (p.Ser222Trp) (rs199472765)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182330 SCV000234633 pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing The S349W mutation was first identified in one individual diagnosed with LQTS (Splawski I et al., 2000) and subsequently identified in 15 individuals from 3 families enrolled in the International LQTS Registry (Horr S et al., 2011). The individuals from this registry who harbored the S349W mutation appeared to experience more cardiac events than individuals who harbored other haploinsufficient mutations, despite having a normal ECG during baseline examination. In vitro functional studies showed S349W had a relatively mild effect on the ion channel current but a pronounced effect on channel activation (Horr S et al., 2011). S349W was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. S349W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Missense mutations in this same residue (S349P) and in nearby residues (G345R, G345E, G345V, G350R, G350V, F351S) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The variant is found in KCNQ1 panel(s).
Invitae RCV001377773 SCV001575195 likely pathogenic Long QT syndrome 2019-04-03 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 349 of the KCNQ1 protein (p.Ser349Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in several individuals affected with long QT syndrome (LQTS) (PMID: 20662986), and in an individual with Jervell and Lange-Nielsen syndrome in combination with a pathogenic variant (PMID: 22539601). ClinVar contains an entry for this variant (Variation ID: 52942). This variant has been reported to affect KCNQ1 protein function (PMID: 20662986). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057538 SCV000089057 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11668638;PMID:14678125;PMID:15840476;PMID:20662986;PMID:17999538;PMID:17470695;PMID:22539601). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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